The genes of the human leukocyte antigen (HLA) region control a variety Of functions involved in the immune response, and influence susceptibility to over 40 diseases. Our understanding of the structure and function of the HLA genes, their disease associations, and the evolutionary features of this multigene family has benefitted from recent advances in molecular biology, immunology, disease modelling and population genetics. Theoretical studies in the development of models to determine the modes of inheritance of the HLA associated diseases have led to a better understanding of the inheritance patterns in insulin dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, hemochromatosis, celiac disease, and others. It is now clear that many of the HLA associated diseases involve heterogeneity in their HLA components, as well as non-HLA genetic components. The specific aims of our research are to study the genetic components in the etiology of the HLA associated diseases, and population genetic features of the HLA system. A variety of methods to test modes of inheritance of diseases using marker allele information, will be developed. Methods appropriate for the analysis of marker systems which are not highly polymorphic, to both detect linkage and determine modes of inheritance, will be investigated. The information content of particular pedigree types for LOD score analysis will be investigated. Two methods using patterns of linkage disequilibrium will be investigated to determine their usefulness in mapping disease predisposing genes. A number of large collaborative data sets of HLA associated diseases will be analyzed. A framework for genetic counselling of HLA associated, and other complex diseases, will be developed. The results of our studies are generally applicable to the mapping and characterization of complex human genetic traits.